Bioequivalence and Bioavailability Forum

Hello Helmut et al

❝ Another point stated (Table 1) is the narrower acceptance range (AUC, Cmax: 90%-111%) for a couple of drugs / drug classes, namely Aminophylline/Theophylline, Lithium, Thyroxine, Warfarin, Antiepileptics apart from benzodiazepines (Lamotrigine: 90%-110%), Immunosuppressives, Antiarrhythmics, Centrally acting anorectics, and Tricyclic antidepressants.

Further to this, I wonder whether you have any specific tips for BE studies with narrow therapeutic index drugs. I've just been playing with NQuery Advisor which tells me that, as we all know very well, for an intra-subject CV of 23.5% I need a minimum of 24 subjects where acceptance limits are 80% to 125%. If, however, I narrow the limits to 90% to 111.1%, I find that for the same CV I'll need 230 subjects. I had not expected this!

I accept that most NTI drugs probably have fairly low intra-subject CVs, but I'm trying to design a study for Levothyroxine where the problem of endogenous levels coupled with the fact that the 600mcg dose does not increase blood levels all that much over baseline means that, in my limited experience anyway, the CVs for AUC can be quite high. [Well over 23.5%.]
Any pearls of wisdom to cast before this swine?

Best regards

Andrew